Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ma, YT; Yang, Y; Cai, P; Sun, DY; Sánchez-Murcia, PA; Zhang, XY; Jia, WQ; Lei, L; Guo, M; Gago, F; Wang, H; Fang, WS.
A Series of Enthalpically Optimized Docetaxel Analogues Exhibiting Enhanced Antitumor Activity and Water Solubility.
J Nat Prod. 2018; 81(3):524-533
Doi: 10.1021/acs.jnatprod.7b00857
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Sánchez Murcia Pedro Alejandro
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- Abstract:
- A dual-purpose strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of C-2- and C-3'-modified analogues. Both aims were realized when the C-3' phenyl group present in docetaxel was replaced with a propargyl alcohol. The resulting compound, 3f, was able to overcome drug resistance in cultured P-gp-overexpressing tumor cells and showed greater activity than docetaxel against drug-resistant A2780/AD ovarian cancer xenografts in mice. In addition, the considerably lower hydrophobicity of 3f relative to both docetaxel and paclitaxel led to better aqueous solubility. A molecular model of tubulin-bound 3f revealed novel hydrogen-bonding interactions between the propargyl alcohol and the polar environment provided by the side chains of Ser236, Glu27, and Arg320.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Antineoplastic Agents, Phytogenic - pharmacology
- Cell Line, Tumor -
- Docetaxel - pharmacology
- Drug Resistance, Neoplasm - drug effects
- Female -
- Mice -
- Mice, Inbred BALB C -
- Mice, Nude -
- Microtubules - metabolism
- Ovarian Neoplasms - drug therapy
- Paclitaxel - pharmacology
- Solubility -
- Tubulin - metabolism
- Water - chemistry